A novel short convergent entry into himbacine derivatives.

Article abstract of DOI:10.1021/ol025801g

[reaction: see text]. The IMDA reaction of 9 leads with good stereoselectivity to exo-adduct 10b. The functionalized ABC-ring core in 10 is well suited for the convergent synthesis of analogues of himbacine, a naturally occurring M2 selective muscarine re

Full text of DOI:10.1021/ol025801g

ORGANIC
LETTERS
2002
Vol. 4, No. 9
1579-1582
A Novel Short Convergent Entry into
Himbacine Derivatives
Gunther Van Cauwenberge, Ling-Jie Gao, Dirk Van Haver, Marco Milanesio,‡
,†
Davide Viterbo,‡ and Pierre J. De Clercq*
Department of Organic Chemistry, Ghent UniVersity, Krijgslaan 281, B-9000 Gent,
Belgium, and Dipartimento di Scienze e Tecnologie AVanzate, UniVersita` del Piemonte
Orientale “A. AVogadro”, Corso T. Borsalino 54, 15100 Alessandria, Italy
pierre.declercq@rug.ac.be
Received March 1, 2002
ABSTRACT
The IMDA reaction of 9 leads with good stereoselectivity to exo-adduct 10b. The functionalized ABC-ring core in 10 is well suited for the
convergent synthesis of analogues of himbacine, a naturally occurring M selective muscarine receptor antagonist, as illustrated with the
2
further synthesis of the dehydro-derivative 5.
Among the piperidine alkaloids that were isolated 46 years
ago from the bark of Galbulimima baccata, a species of the
magnolia family found in New Guinea and parts of Australia,
himbacine (1), himbeline (2), himandravine (3), and him-
gravine (4) possess an interesting tetracyclic structure,
basically consisting of an ABC-ring part to which is
connected, by an (E)-double bond, a 2,6-disubstituted pip-
eridine D-ring.1 These natural derivatives have been recent
targets for total synthesis,2,3 in particular when it became
known that himbacine is a potent muscarinic receptor
antagonist with selectivity for the M2 receptor.4 Since the
blocking of presynaptic muscarinic receptors may contribute
to the treatment of diseases in which the central cholinergic
system degenerates,5 the development of highly selective and
potent M2 antagonists is desirable.6 So far structure-function
relationship studies have shown that the deletion of substan-
G.; De Clercq, P. J. Tetrahedron Lett. 1995, 36, 7515. Also see: Hofman,
S.; De Baecke, G.; Kenda, B.; De Clercq, P. J. Synthesis 1998, 479. (f)
Baldwin, J. E.; Chesworth, R.; Parker, J. S.; Russell, T. Tetrahedron Lett.
1995, 36, 9551.
(3) For a total synthesis of himandravine, see: Chackalamannil, S.;
Davies, R.; McPhail, A. T. Org. Lett. 2001, 3, 1427.
(4) (a) Darroch, S. A.; Taylor, W. C.; Choo, L. K.; Mitchelson, F. Eur.
J. Pharmacol. 1990, 182, 131. (b) Miller, J. H.; Aagaard, P. J.; Gibson, V.
A.; McKinney, M. J. Pharmacol. Exp. Ther. 1992, 263, 663. For a
classification of muscarine receptor subtypes, see: (c) Levey, A. I. Life
Sci. 1993, 52, 441.
(5) (a) Coyle, J. T.; Price, D. L.; DeLong, M. R. Science 1983, 219,
1184. (b) Mash, D. C.; Flynn, D. D.; Potter, L. T. Science 1985, 228, 1115.
(6) (a) Kozikowski, A. P.; Fauq, A. H.; Miller, J. H.; McKinney, M.
Bioorg. Med. Chem. Lett. 1992, 2, 797. (b) Malaska, M. J.; Fauq, A. H.;
Kozikowski, A. P.; Aagaard, P. J.; McKinney, M. Bioorg. Med. Chem. Lett.
1993, 3, 1247. (c) Malaska, M. J.; Fauq, A. H.; Kozikowski, A. P.; Aagaard,
P. J.; McKinney, M. Bioorg. Med. Chem. Lett. 1995, 5, 61. (d) Doller, D.;
Chackalamannil, S.; Czarnicki, M.; McQuade, R.; Ruperto, V. Bioorg. Med.
Chem. Lett. 1999, 9, 901. Also see ref 4a.
† Ghent University.
‡ Universita` del Piemonte Orientale “A. Avogadro”.
(1) (a) Brown, R. F. C.; Drummond, R.; Fogerty, A. C.; Hughes, G. K.;
Pinhey, J. T.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1956, 9, 283. For
a review, see: (b) Ritchie, E.; Taylor, W. C. The Alkaloids; Manske, R. H.
F., Ed.; Academic Press: New York, 1967; Vol. 9, p 529.
(2) For the total synthesis of himbacine, see: (a) Hart, D. J.; Wu, W.-
L.; Kozikowski, A. P. J. Am. Chem. Soc. 1995, 117, 9369. Also see: Hart,
D. J.; Li, J.; Wu, W. L.; Kozikowski, A. P. J. Org. Chem. 1997, 62, 5023.
(b) Chackalamannil, S.; Davies, R. J.; Asberom, T.; Doller, D.; Leone, D.
J. Am. Chem. Soc. 1996, 118, 9812. Also see: Chackalamannil, S.; Davies,
R. J.; Wang, Y.; Asberom, T.; Doller, D.; Wong, J.; Leone, D.; McPhail,
A. T. J. Org. Chem. 1999, 64, 1932. (c) Takadoi, M.; Katoh, T.; Ishiwata,
A. Terashima, S. Tetrahedron Lett. 1999, 40, 3399. (d) Hofman, S.; Gao,
L.-J.; Van Dingenen, H.; Hosten, N. G. C.; Van Haver, D.; De Clercq, P.
J.; Milanesio, M.; Viterbo, D. Eur. J. Org. Chem. 2001, 2851. For early
studies directed toward the total synthesis of himbacine, see: (e) De Baecke,
10.1021/ol025801g CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/02/2002

tial parts of the skeleton and/or functionality results in loss
of affinity and/or selectivity.6 Hence we became interested
in the synthesis of substances that are isomeric with the
natural derivatives.2d In this context we wish to describe here
a short convergent approach that is well suited for analogue
development, as illustrated with the enantioselective synthesis
of (-)-dehydrohimbacine (5).
diene (10 to 11).8 The latter reaction type is also used in the
construction of the Diels-Alder precursor 9. Hence central
in the synthesis stands a geminal substituted dibromo alkene
(6), the halogen atoms in which are both used in establishing
key C-C bonds via palladium-catalyzed cross-coupling
reactions with the vinylstannanes 7 and 8. So far the Diels-
Alder cycloaddition has been the preferred pathway for the
synthesis of the ABC-ring skeleton.2,3 Indeed, among the four
different reported strategies,2a-d one involves an inter-
molecular cycloaddition2c and the others proceed via in-
tramolecular versions centering around two different bond
constructions. The present approach constitutes a third
unprecendented construction set.
The synthesis of (-)-5 is outlined in Scheme 2.9 The
enantioselective preparation of Diels-Alder precursor 9 starts
with (S)-ethyl lactate, which is converted to the geminal
substituted dibromide 6 via a three-step sequence involving
protection of the hydroxy group as tert-butyldimethylsilyl
ether (12), reduction of the ester to the aldehyde 13, and
subsequent olefination to 6 (59% overall).10 The first Stille
coupling in the scheme involves reaction of 6 with vinyl-
stannane 7.11 The use of the Stille reaction in the stereo-
specific conversion of 1,1-dibromo-1-alkenes with vinyl-
stannanes to yield (Z)-monobromides has been studied in
detail by Shen and Wang.12 By using their optimized
conditions (Pd2dba3 7 mol %, tris(2-furyl)phosphine (TFP),
toluene, reflux, 4 h), bromodiene 15 is obtained in 71% yield.
After further deprotection to alcohol 16, the latter is
converted to the required acrylate (68% yield).
The projected Diels-Alder reaction (9 to 10) involves as
precursor a 3-bromo-4,5-dialkylpentadienyl acrylate carrying
a stereocenter at the allylic 1-position of the tether. In practice
when 9 is heated at 185 °C for 22 h (toluene, TEMPO,
DIPEA), a mixture of two among the four possible adducts
is obtained next to some starting material (8%). After
chromatographic purification, the two adducts, 10a and 10b
are obtained in 11% and 68% isolated yield, respectively.
The unambiguous structural assignment of both adducts
follows from (1) the X-ray crystallographic determination
of the structure of crystalline 10b revealing a trans-fused
γ-lactone (Figure 1)13 and (2) the observation that, upon basic
treatment, 10b isomerizes to adduct 10a with a more stable
cis-fused γ-lactone. This experimental result is in accord with
As shown in Scheme 1 our synthetic strategy rests on two
key transformations. First, an intramolecular Diels-Alder
reaction (IMDA)7 involving a substituted pentadienyl acrylate
to provide in a single step the required unsaturated ABC-
ring skeleton (9 to 10). Second, attachment of the D-ring
involving a Stille cross-coupling reaction to yield the required
Scheme 1
(7) For reviews on the IMDA reaction, see: (a) Fallis, A. G. Can. J.
Chem. 1984, 62, 183. (b) Ciganek, E. Org. React. 1984, 32, 1. (c) Craig,
D. Chem. Soc. ReV. 1987, 187. (d) Roush, W. R. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon:
Oxford, 1991; Vol. 5, p 513.
(8) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Farina,
V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1.
1
(9) All intermediates were characterized by H and 13C NMR, IR, and
mass spectroscopic methods.
(10) (a) Trost, B. M.; Mueller, T. J. J. J. Am. Chem. Soc. 1994, 116,
4985. (b) Ku, Y.-Y.; Patel, R. R.; Elisseou, E. M; Sawick, D. Tetrahedron
Lett. 1995, 36, 2733. (c) Marshall, J. A.; Xie, S. J. Org. Chem. 1995, 60,
7230.
(11) The synthesis of cyclohexenyltrimethylstannane (7) involves the Pd-
(0)-catalyzed reaction of 1-cyclohexenyl triflate and hexamethylditin (Pd-
(Ph3)4, LiCl, THF, 60 °C, 79% yield), according to: Wulff, W. D.; Peterson,
G. A.; Banta, W. E.; Chan, K. S.; Faron, K. L.; Gilbertson, S. R.; Kaesler,
R. W.; Yang, D. C.; Murray, C. K. J. Org. Chem. 1986, 51, 277.
(12) (a) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873. See also:
(b) Uenishi, J.; Matsui, K. Tetrahedron Lett. 2001, 42, 4353.
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Org. Lett., Vol. 4, No. 9, 2002

Scheme 2a
Figure 1. X-ray crystal structure of 10b.
The stereochemical outcome of the cycloaddition is
determined by (1) the endo or exo mode of addition and (2)
the anti or syn approach of the dienophile relative to the
orientation of the methyl group at C-1 (Scheme 3). Steric
Scheme 3
a Reaction conditions: (a) DIBAL-H, toluene, -78 °C (80%);
(b) PPh3, CBr4, CH2Cl2, -78 °C (78%); (c) (Me3Sn)2, Pd(PPh3)4,
LiCl, THF, 60 °C (84%); (d) Pd2dba3 (0.07 equiv), TFP (0.3 equiv),
toluene, 110 °C, 4 h (71%); (e) TBAF, THF, rt (88%); (f)
CH2CHC(O)Cl, DIPEA, CH2Cl2, -50 °C (77%); (g) 185 °C,
toluene, TEMPO, DIPEA, 24 h (79%); (h) NaH, THF, rt (82%);
(i) n-BuLi, Bu3SnH, CuCN, THF, -78 °C, 1 h (80%); (j) Pd2dba3,
TFP, DIPEA, toluene, 110 °C, 2 h (80%); (k) TFA, CH2Cl2, 37%
aq CH2O, NaCNBH3 (81%).
the relative steric energies that were calculated for the
different stereoisomers 10a, 10b, 10c, and 10d: 0.0, 9.9,
3.3, and 14.6 kJ mol-1, respectively.14
considerations, in particular the interaction of the large Br
with the substituents at C-1, are clearly in favor of the anti
approach shown in the scheme. The preferred exo mode (ratio
(13) It is worth noting that it was possible to confirm the correct
enantiomeric configuration by refinement of the absolute structure parameter,
see: Flack, H. D. Acta Crystallogr. 1983, A39, 876. Crystallographic data
(excluding structure factors) for the structure reported in this paper have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-180241. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, U.K. [Fax: int.code +44 (1223) 336-033. E-mail: deposit@
ccdc.cam.ac.uk].
Org. Lett., Vol. 4, No. 9, 2002
1581

exo:endo ) 6.2:1) is in line with previous results that were
obtained with several related pentadienyl acrylates.15 In
particular the recent conformational studies of the IMDA
reaction of C-1 substituted derivatives by White and Snyder15b
and Paddon-Row and Sherburn15c are enlightening. In these
examples the thermal reaction led to the formation of
cycloadducts that correspond to the diastereomeric configu-
rations a, b, and c with the preferred formation of trans-
fused b (stereochemical designations as in Scheme 3). It is
interesting to note that both groups confirmed the obtained
experimental results by combined force field and density
functional calculations (Becke3LYP/6-31G(d) level) on
model transition structures of their reactions.
In conclusion, a short, efficient entry into the ABC-ring
skeleton of himbacine-like derivatives has been developed.
In its longest linear sequence 7 steps are involved for the
synthesis of vinylic bromide intermediates (10), which are
well suited for the subsequent attachment of the piperidine
D-ring via a palladium-catalyzed cross-coupling reaction. The
C-C bond construction set involves two Stille couplings and
one intramolecular Diels-Alder reaction. The stereochemical
outcome of the latter was found to be in accord with recent
literature reports. The further potential of the unsaturated
bromide 10 in analogue development using cross-coupling
reactions will be reported in a full account.
The final sequence to 5 first involves a second Stille
reaction. Cross-coupling between vinylic bromide 10a and
vinylstannane 8 affords diene 11a in 80% isolated yield (Pd2-
dba3, TFP, DIPEA, toluene, reflux, 2 h).16 After removal of
the N-Boc protective group (TFA, CH2Cl2), the N-Me group
is introduced via a classical reductive amination (CH2O,
NaCNBH3) to afford 5 in 81% isolated yield.
Acknowledgment. G.V.C. thanks the IWT (Instituut voor
Wetenschappelijk en Technologisch Onderzoek) for a fel-
lowship.
Supporting Information Available: 1H and 13C NMR
spectra for compounds 6, 15, 16, 9, 10a, 10b, 11a, and 5
and X-ray crystallographic data for 10b. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Calculated by the MM2* force field implementation of MacroModel,
see: MacroModelsAn Integrated Software System for Modeling Organic
and Bioorganic Molecules using Molecular Mechanics. Mohamadi, F.;
Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.;
Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440.
(15) (a) He, J.-F.; Wu, Y.-L. Tetrahedron 1988, 44, 1933. (b) White, J.
D.; Demnitz, F. W. J.; Oda, H.; Hassler, C.; Snyder, J. P. Org. Lett. 2000,
2, 3313. (c) Turner, C. I.; Williamson, R. M.; Paddon-Row: M. N.;
Sherburn, M. S. J. Org. Chem. 2001, 66, 3963.
OL025801G
(16) The synthesis of vinylstannane 8 involves the addition of a higher
order tributyltin cuprate to the known propargylic amine 17,2d according to
(a) Capella, L.; Degl’Innocenti, A.; Mordini, A.; Reginato, G.; Ricci, A.;
Seconi, G. Synthesis 1991, 1201. (b) Heutringer, M. H.; Singer, R. D.;
Oehlschlager, A. C. J. Am. Chem. Soc. 1990, 112, 9397.
1582
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